Orkambi Gets FDA Approval

Today the FDA approved the combination of Vertex's Lumacaftor and Kalydeco (Orkambi) for cystic fibrosis people, 12 years and older, with two copies (homozygous) of the F508del mutation. We originally wrote about Orkambi here Vertex Pharmaceutical Passes Advisory Committee, when they were front and center with the FDA advisory committee.

Orkambi has been appoved for CF patients despite the relatively small improvement in FEV1 in two F508del clinical studies.  How high is the bar set for other companies to get clinically significant improvement over Kalydeco as mono therapy for the G551D mutation, and Orkambi combination therapy, for patients 12 years and older, with two copies of the F508del mutation?

G551D Through 24 weeks Kalydeco 150 mg q12h

• 10.6% and 12.5% FEV1 improvement vs. placebo

G551D Through 48 weeks Kalydeco 150 mg q12h

• 10.5% and 10.0% FEV1 improvement vs. placebo
• 3,000 Worldwide Patients

F508del Through 24 weeks 2 tablets (ivacaftor 125 mg / lumacaftor 200 mg) q12h

• 2.6% and 3.0% FEV1 improvement vs. placebo
• 26,000 U.S. + EU Orkambi Patient Potential

These are the FEV1 (forced expired volume) numbers that other companies will be considering as significant, to improve current therapy for CF patients.  The side effect profile was mild, as a high percentage of patients completed the Vertex clinical trials.  The annual wholesale acquisition cost (WAC) will be priced at around $259,000 per patient for the Orkambi combination.  Thank you for reading.
 

NMDA Receptor Modulators for Depression

NMDA (N-mythel-D-asparate) roots track back to a drug known as Ketamine or street name Special K, with hallucination effects.  Ketamine is an NMDA receptor antagonist originally used as an anaesthetic.  The glutamate receptor subtype known as (NMDA) plays a central role of modulating brain activity in the central nervous system, such as synaptic transmission, synaptic plasticity, and excitotoxicity. Pharmaceutical firms have been developing NMDA type drugs for over two decades, and a few including Memantine, and Nuedexta are being marketed for other indications outside of depression.
There have been several studies modulating the NMDA receptor, that have shown efficacy in patients with treatment-resistant depression.  A trial performed by Avanir Pharmaceuticals for pseudobulbar affect with drug AVP-923 (Nuedexta), showed efficacy in a subset of patients for depression using the Beck Depression Inventory II or BDI-II. Data showed that the dextromethorphan (an NMDA receptor antagonist, sigma 1 agonist) / quinidine combination was effective in patients with BDI-II scores greater than 18 at inclusion with AVP-923 30/10, and was associated with a statistically significant improvement of (p=0.03). What's also significant is that major depression was an exclusion into the trial.  Avanir is now in a phase 2 clinical trial with AVP-786, for major depressive disorder patients as adjunct to current antidepressant here NCT02153502.  I think the chances of success are high, based on how the dextromethorphan/quinidine combination performed in the subset of patients in prior trials.
Private company Naurex, is also working on NMDA drugs for depression patients. The company has displayed good data in early clinical trials using IV, and soon to be launched an oral NMDA drug for depression.  Thank you for reading.

AVP-786 is Concert Pharmaceutical's deutered enhanced version of AVP-923.

Concert Pharmaceuticals: ($16.91)

Quick technical look at Concert Pharmaceuticals with a daily chart below. Everyday the stock closes higher, a new all-time closing high is achieved.

The out performance is evident when shown on a chart that has the XBI Small Cap Biotechnology Fund, and the S&P 500 below over a five day period.  

Bottom Line:  Funds are adding shares, as they see future value at these prices.
Thank you for reading.

AVP-923 and AVP-786

Avanir Pharmaceuticals with drug AVP-923 completed a very successful phase 2 trial for symptoms of agitation in Alzheimer's patients.  Avanir now under the Otsuka umbrella, is conducting two phase 3 trials with the deuterated version of AVP-923, known as AVP-786 for the same patients.  So what are the drug dose differences and exclusion criterias between the successful phase 2 AVP-923 clinical study, and the AVP-786 phase 3 clinical trials for the treatment of agitation in patients with dementia of the Alzheimer's type?

AVP-923  NCT01584440
Phase 2 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 20 mg / Quinidine 10 mg
Dextromethorphan 30 mg / Quinidine 10 mg

Exclusion Criteria:

• Patient has other type of dementia (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia).
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g. malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, certain cardiac conduction abnormalities including QTc prolongation, or unstable valvular heart disease).
• Patients with myasthenia gravis.

AVP-786   NCT02442765, NCT02442778
Phase 3 for the treatment of agitation in patients with dementia of the Alzheimer's type.
Dextromethorphan 28 mg / Quinidine 4.9 mg
Dextromethorphan 18 mg / Quinidine 4.9 mg

Exclusion Criteria:

• Patient has dementia predominantly of non-Alzheimer's type (e.g., vascular dementia, frontotemporal dementia, Parkinson's disease, substance-induced dementia)
• Patients with co-existent clinically significant or unstable systemic diseases that could confound the interpretation of the safety results of the study (e.g., malignancy, poorly controlled diabetes, poorly controlled hypertension, unstable pulmonary, renal or hepatic disease, unstable ischemic cardiac disease, dilated cardiomyopathy, or unstable valvular heart disease)
• Patient with myasthenia gravis

The difference in the exclusions from the phase 2 AVP-923 trial and the deutered version using AVP-786 is that QTc prolongation, which was an exclusion in the phase 2 is not listed in the current phase 3 trials.  The reduction in the dose of quinidine to 4.9 mg from 10 mg could be the prime reason for the two new phase 3 trials not including QTc prolongation as an exclusion criteria.  I expect these two phase 3 trials to recruit at a much faster rate, than the AVP-923 trial achieved. I also expect that patients currently taking AVP-923 for other indications, will eventually switch to the deutered version AVP-786, which has a similar PK profile to AVP-923, favorable dosing, and has a longer patent that extends to 2030 US and 2028 EU. Thank you for reading.

What is a 505(b)(2) New Drug Application

A 505(b)(2) application differs from a typical new drug application, in that the process to approval could potentially be quicker with less expense.  The 505(b)(2) process takes drugs that have already been approved and makes small modifications to them. Typically a company will perform a phase 1 bridging study to compare the systemic levels of the proposed drug product and the reference product.  A bridging study also allows a company to reference the safety and efficacy information that is known for the original drug.
There are three advantages for a company that pursues a 505(b)(2) application.
1.  It is a relatively lower risk process because the original drug may have already been proven to be safe.
2.  The entire process is lower cost.
3.  The pathway to approval can be quicker because of the fewer studies required.
Companies such as Auspex, and Concert Pharmaceuticals, who attempt to improve the metabolic, safety, or efficacy profile with the use of deuteration, could benefit greatly by following the pathway of a 505(b)(2) submission application to get to market quicker, with less expense.  As those drugs get approved quicker, with less expense, the benefit should fall to the patient in need, and our medical healthcare system that provides insurance coverage.  Thank you for reading.

Vertex Pharmaceuticals Passes Advisory Committee

Vertex's (VRTX) drug combo named Orkambi faced the advisory committee on Tuesday this week. The FDA document is here Orkambi Advisory Committee .  The advisory committee voted 12-1 to approve the combination for patients with Cystic Fibrosis who have two copies (homozygous) of the F508del mutation, 12 years and older.  So that opens their market to a substantially much larger population of 20,000 patients. The results from the two phase 3 studies 890-103 and 890-104 are as follows.

Study 809-103

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 2.6% mean absolute improvement over placebo on FEV1 test.

 

Study 809-104

Lumacaftor 400 mg + Ivacaftor 250 mg q12 at week 24 = 3.0% mean absolute improvement over placebo on FEV1 test.

Orkambi 

Lumacaftor 200 mg + Ivacaftor 125 mg, proposed dose every 12 hours.

Lumacaftor and Ivacaftor was administered twice daily, with the safety profile seen as well tolerated. What's intriguing is the fact that Orkambi the proposed combo up for FDA approval is administered as Lumacaftor 200 mg, and Ivacaftor as 125 mg twice daily. In prior trials, Lumacaftor dosages at the 600 mg level, achieved better efficacy than the 400 mg Lumacaftor dose on FEV1.  The reason for using 400 mg instead of 600 mg, is because the drug-drug interaction of Lumacaftor tends to lessen the effects of Ivacaftor up to 80% as dosages increase. The final date for FDA approval falls on July 5th, of 2015, and in the fourth quarter for EU approval. With an annual therapy per patient price of around $300,000, the potential to achieve revenue up to six billion is attainable. Thank you for reading.                                                                                                                       

Patent Infrigement: Obvious or Nonobvious

As companies file for new chemical entity patents, the question of infringement on an existing drug becomes either obvious or nonobvious.  This link to an article titled Deuterated Drugs: Unexpectedly Nonobvious? is a nice paper by Ms. Kristen Buteau on what constitutes obvious from nonobvious inventions, and how it relates to drug companies such as Auspex, and Concert Pharmaceuticals.  The company that is applying for a new patent must present an unexpected difference between the claimed structures and the prior art. That difference may be the new drugs unexpected metabolism rate, other pharmacokinetic advantages, or a reduced dosing regimen compared to the prior drug.  But any unexpected difference must not be obvious, must be a skill or art in itself, such as the placing of deuterium on a drug that could have many options to choose from, potentially thousands, as the drug Cymbalta has.

Concert Pharmaceuticals is currently in a phase 1 trial to test d-Ivacaftor, which is the deuterated version of Ivacaftor, a drug that is currently approved for the treatment of Cystic Fibrosis.  Not only was the deuterated drug (d-Ivacaftor) patent filed before any mention of deuterium from Vertex Pharmaceutical, but the unexpected differences in pre-clinical studies suggest, that the deutered Ivacaftor version from Concert, improved pharmacokinetics to a high degree, both in-vitro and in-vivo, and may have the convenience of single 24 hour dosing compared to twice daily.  This phase 1 trial will show how (deuterated) d-Ivacaftor does in it's first in human clinical trial on safety, tolerability, and PK, versus the placebo Ivacaftor, and demonstrate whether some of the pre-clinical results are equally impressive in healthy human subjects. Thank you for reading.

Contact:  586-431-8000

Deuterated Drugs For Hematologic Diseases

Concert Pharmaceutical is actively pursuing patent applications for deuterated drugs for hematologic diseases.  The company has run a pre-clinical drug trial for the deutered lenalidomide (Concert drug named CTP-221), and is pursuing patents related to Rigosertib, a drug that is used by Onconova (ONTX) in clinical trials. Each drug is primarily directed toward some form of  Myelodysplastic Syndrome (MDS) or AML.
Lenalidomide was approved in 2005 for low to intermediate-1 risk MDS with deletion 5-q chromosomol abnormality.
Rigosertib has been used in several clinical trials as both monotherapy and as co-therapy, intravenously and orally, primarily for intermediate-2 to higher risk MDS, and for patients who have failed prior therapies. For some of these patients who have failed previous therapy (refractory MDS), the prognosis is less than 12 months survival, and the drug side effect profile is quite adverse.  
I really like the direction CNCE is taking in pursuing patents for hematological indications such as intermediate-2 to higher risk MDS, where there remains an un-met need for longer and better tolerated drug therapies.  I am looking one to two years out into the future direction of the company, and believe Concert may be able to get both of these deutered hematological drugs into clinical trials for different MDS patients in 2016, after all patents have been secured.  At this time we do not know if CTP-221 will ever make clinical trials due to competing patent issues.  Thank you for reading.

Concert Pharmaceuticals: JZP-386

JZP-386 is the deutered enhanced version of sodium oxybate or commercial drug known as Xyrem, which is manufactured by Jazz Pharmaceuticals.  The drug was approved in 2002 for cataplexy in narcolepsy, and 2005 for excessive daytime sleepiness (EDS) in narcolepsy.  The patents run from 2019 through 2024 at the latest.  Xyrem is administered twice daily as a liquid dose, once before bed and again after about four hours of sleep. Xyrem has a side effect profile that includes headaches, dizziness, nausea, and potentially more serious side effects in higher doses such as convulsions, respiratory depression, coma and death, according to Xyrem prescribing information.   Concert is currently in a phase 1 trial to evaluate the deutered Xyrem version called JZP-386, compared to Xyrem, with a readout on the trial any day now.  The goal of the deutered version JZP-386, could be once daily dosing, lower dosing, or a reduction in side effects that currently exists with Xyrem. Concert would have a chance to receive royalties that run from mid single digits to low double digits, not to exceed 20% on a country-by-country basis, and licensed product-by-licensed product basis. The patent for JZP-386 runs from 2030 to 2032, U.S. EU, and Japan. Thank you for reading.

What is CTP-221

CTP-221 is the deutered enhanced drug for lenalidomide, or commercial drug known as Revlimid, which is manufactued by Celgene.  The drug targets indications in Myelodysplastic Syndrome (MDS) and Multiple Myeloma amongst others, and is expected to produce revenue up to seven billion annually for the company. This is the second Celgene drug after CTP-730 that Concert may consider for clinical trials. The patent for Revlimid runs through 2026. CTP-221 has shown to be approximately 5-6 fold greater potency in animal models with similar antitumor effects.  Thank you for reading.
 

What is CTP-730

CTP-730 is the deutered enhanced version of Otezla (Apremilast), that is manufactured by Celgene.  The drug was approved in March of 2014 for psoriatic arthiritis, and again in September of 2014 for moderate to severe plaque psoriasis. The patent for Otezla runs until 2024 US and EU.  The drug is forecasted to bring in around $2 billion in revenue by 2020. The typical dose is 30 mg twice daily, and the drug is known to exhibit side effects such as diarrhea, nausea, and headache. A deuterated version could potentially reduce the dosage to once daily, improve the efficacy, and side effect profile.
Concert is currently in phase 1 testing to explore the safety and pharmacokinetics profile compared to placebo with a full readout around September 2015.  Once the trial is complete a one time $8 million milestone will be awarded to Concert from Celgene. More importantly, will be the trial results....the first in human trials for CTP-730.  The relevance for increased efficacy, or safety with a once a day tablet, would be valuable to Celgene, not to mention the increased patent life that the D-Apremilast version would have, to 2030. Thank you for reading.  
                                                                                       

Deuteration Validation

On March 30th, Teva Pharmaceuticals agreed to acquire Auspex Pharmaceuticals for $3.5 billion, or around $100.00 per share.  A few points to consider as it relates to Concert Pharmaceuticals, which is one of our holdings.

1. This acquisition instills confidence in the science of deuterium-based chemistry.  Both Auspex and Concert are applying deuterium to existing drugs to potentially enhance their efficacy, half-life or safety profile.
2. In 2011 Concert assigned patent rights for the deuterated drug Pirfenidone to Auspex.  Under the agreement, if a change in control of ASPX, Concert would be due 1.44% of the purchase price, in this case, approximately $50 million.
3.  After completing a recent secondary offering for up to $46 million and considering the newly acquired $42 million, the company should hold approximately $154 million, after retiring $7 million in debt.  Thank you for reading.